Cardiovascular development: towards biomedical applicability: Regulation of cardiomyocyte differentiation of embryonic stem cells by extracellular signalling

Investigating the signalling pathways that regulate heart development is essential if stem cells are to become an effective source of cardiomyocytes that can be used for studying cardiac physiology and pharmacology and eventually developing cell-based therapies for heart repair. Here, we briefly describe current understanding of heart development in vertebrates and review the signalling pathways thought to be involved in cardiomyogenesis in multiple species. We discuss how this might be applied to stem cells currently thought to have cardiomyogenic potential by considering the factors relevant for each differentiation step from the undifferentiated cell to nascent mesoderm, cardiac progenitors and finally a fully determined cardiomyocyte. We focus particularly on how this is being applied to human embryonic stem cells and provide recent examples from both our own work and that of others

Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors

Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT1) and type 2 (AT2). In rodents, two AT1subtypes were identified (AT1aand AT1b). To determine receptor-specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT1subtypes. All combinations lacking AT1awere distinguished by reduced heart rate. AT1adeletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT1band/or AT2had no effect. However, the additional lack of AT1bin AT1a-deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the reninangiotensin system and to search for angiotensin II effects independent of AT1and AT2